The intestines are lined by a single layer of epithelial cells that constitute a barrier between our bodies and the contents of our gastrointestinal tract. Ulcerative colitis and Crohn's disease are autoimmune conditions collectively known as idiopathic inflammatory bowel disease. An emerging model of the pathogenesis of inflammatory bowel disease suggests there are 3 essential factors: (1) a breakdown in intestinal barrier function;(2) exposure of luminal contents to the intestinal immune cells;and (3) an exaggerated immune response. The development of therapies that specifically target repair of intestinal barrier dysfunction have clear potential for the treatment of inflammatory bowel disease as an adjunct or alternative to current immune- based therapies. Gastrokine-1 is a naturally occurring gut hormone that is mitogenic and motogenic in murine gastrointestinal epithelial cells. Preliminary studies show that a 22-mer peptide derivative of gastrokine-1 hormone is effective at reversing chemically-induced intestinal inflammation and strengthening intestinal barrier function in mice. The objectives of the proposed research are to: 1) test the efficacy of gastrokine-1 peptide at reversing inflammation and restoring barrier function in mouse models of IBD and 2) identify the essential role(s) of GKN1 through study of a GKN1 knockout mouse. The methods used in the proposed research will utilize different mouse models of IBD. We currently utilize multiple mouse models of IBD, including the IL-10-/- mouse, the T cell transfer mouse model, and the TNFAIP3-/- mouse model. The ability of GKN1 peptide to reverse IBD in these mouse models will be tested by injecting GKN1 peptide into the mice for one to two weeks and assessing the integrity of the barrier, activation state of the gut immune system and overall health of the animal. GKN1-/- mice will be used to study the essential role of GKN1. The GKN1-/- phenotype will be studied under standard conditions and under inflammatory stressors. The overall significance of this study is to understand the mechanism of action of GKN1 peptide that leads to its beneficial effects on barrier function. Such knowledge will ultimately help us to refine GKN1 peptide, maximize its effectiveness, and guide future efforts to create drugs that specifically target intestinal barrier dysfunction to treat human inflammatory bowel disease. PUBLIC HEALTH RELEVANCE: Crohn's disease and ulcerative colitis are inflammatory bowel diseases that are associated with gastrointestinal barrier weakness, or commonly termed "leaky gut". Gastrokine-1 is naturally occurring human hormone that increases gastrointestinal barrier strength and therefore, may have therapeutic benefit in inflammatory bowel disease. The proposed research will test the effect of gastrokine-1 at improving gastrointestinal barrier function and treating inflammatory diarrheal diseases.